DNA Methylation and Genetic Aberrations in Gastric Cancer

Abstract

<b><i>Background:</i></b> Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. GC is a pathologically and molecularly heterogeneous disease. DNA hypermethylation in promoter CpG islands causes silencing of tumor-suppressor genes and thus contributes to gastric carcinogenesis. In addition, various molecular aberrations, including aberrant chromatin structures, gene mutations, structural variants, and somatic copy number alterations, are involved in gastric carcinogenesis. <b><i>Summary:</i></b> Comprehensive DNA methylation analyses revealed multiple DNA methylation patterns in GCs and classified GC into distinct molecular subgroups: extremely high-methylation epigenotype uniquely observed in GC associated with Epstein-Barr virus (EBV), high-methylation epigenotype associated with microsatellite instability (MSI), and low-methylation epigenotype. In The Cancer Genome Atlas classification, EBV and MSI are extracted as independent subgroups of GC, whereas the remaining GCs are categorized into genomically stable (GS) and chromosomal instability (CIN) subgroups. EBV-positive GC, exhibiting the most extreme DNA hypermethylation in the whole human malignancies, frequently shows <i>CDKN2A</i> silencing, <i>PIK3CA</i> mutations, <i>PD-L1/2</i> overexpression, and lack of <i>TP53</i> mutations. MSI, exhibiting high DNA methylation, often has <i>MLH1</i> silencing and abundant gene mutations. GS is generally a diffuse-type GC and frequently shows <i>CDH1/RHOA</i> mutations or <i>CLDN18–ARHGAP</i> fusion. CIN is generally an intestinal-type GC and frequently has <i>TP53</i> mutations and genomic amplification of receptor tyrosine kinases. <b><i>Key Messages:</i></b> The frequency and targets of genetic aberrations vary depending on the epigenotype. Aberrations in the genome and epigenome are expected to synergistically interact and contribute to gastric carcinogenesis and comprehensive analyses of those in GCs may help elucidate the mechanism of carcinogenesis.

Epstein–Barr Virus—Associated Malignancies and Immune Escape: The Role of the Tumor Microenvironment and Tumor Cell Evasion Strategies

“…DNA hypermethylation of genes has been described in various diseases [52]. Global DNA methylation changes toward increased CpG island hypermethylation were found in human immortalized normal oral keratinocytes after EBV infection [117] and also in EBVassociated malignancies [118]. Thus, DNA methylation affects both the host and the EBV genome.…”

Integrated analysis of expression, prognostic value and immune infiltration of GSDMs in hepatocellular carcinoma

“…DNA methylation is a crucial part of the post-transcriptional modification that can negatively regulate gene expression, thereby get involved in the initiation and progression of cancer [ 19 , 20 ]. We utilized the DiseaseMeth database here to further investigated the DNA methylation level of each GSDM family member in HCC tissues and made the comparison with that in normal liver tissues.…”

Molecular classification reveals the diverse genetic features and prognosis of gastric cancer: a multi-omics consensus ensemble clustering

“…In patients with resectable primary GC, MSI serves as a robust biomarker that indicates favourable post-surgical survival outcomes[13]. GS is generally a diffuse GC, in which CDH1 and RHOA mutations are detectable or frequently show CLDN18-ARHGAP fusion[14]. Moreover, TP53 mutations are found in 70% of CIN GCs, which may result in aneuploidy and focused amplification of receptor tyrosine kinases[15].…”